Malignant mesothelioma is a locally invasive and rapidly fatal neoplastic disease, linked to asbestos exposure.
There are many genetic defects that contribute to the outcome of mesothelioma. Homozygous deletion of p16/CDKN2A (cyclin-dependent kinase inhibitor 2A) is found in approximately 75% of mesotheliomas and may be the most common genetic alteration in this cancer [Hirao T, Bueno R, Chen C J, Gordon G J, Heilig E, Kelsey K T. Carcinogenesis 2002; 23(7):1127-1130; Whitson B A, Kratzke R A. Cancer Lett 2006; 239(2):183-189]. In terms of prognosis, p16/CDKN2A loss is associated with a more aggressive clinical behavior of mesotheliomas [Kobayashi N, Toyooka S, Yanai H, Soh J, Fujimoto N, Yamamoto H, et al. Lung Cancer 2008 62(1):120-5; Davidson B, Reich R, Lazarovici P, Florenes V A, Risberg B, Nielsen S, Lung Cancer 2004; 44(2):159-165.].
The p16 protein leads to cell cycle arrest in the G1 phase by inhibiting cyclin dependent kinase. As a consequence of the lack of p16/CDKN2A, the G1 to S checkpoint control is lost, resulting in a hyperphosphorylation of the tumor suppressor Retinoblastoma (pRb) and cell progression to S phase.
In addition, also the Thropomyosin Receptor Kinase A (TRKA) plays a significant role in the biology of this disease. In fact, frequent expression of activated TRKA (P-TRKA) is frequently found in malignant mesothelioma and is predominantly seen in effusions and in peritoneal lesions, tumors that appear in younger patients [Whitson B A, Kratzke R A. Molecular pathways in malignant pleural mesothelioma. Cancer Lett 2006; 239(2):183-189].
The incidence of mesothelioma worldwide is increasing and only a minority of patients can benefit from a surgical resection. For patients who are not amenable to curative resection, median overall survival is around 6-7 months. Therapeutic options are limited. Most patients, either treated or untreated, die of complications from local disease. Marketed chemotherapeutic agents, as a single agent or in combination, did not prove able to significantly impact survival.
Current therapeutic options include the use of pemetrexed (marketed under the trademark ALIMTA®) as a single agent, that has demonstrated a moderate response rate of 14.1% and a median overall survival of 10.7 months [Scagliotti G V, Shin D M, Kindler H L, Vasconcelles M J, Keppler U, Manegold C, et al. J Clin Oncol 2003; 21(8):1556-1561] or combinations with platinum derivatives (cisplatin or carboplatin) plus pemetrexed [Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, et al. Ann Oncol 2008; 19:370-373].
There are no approved agents for second-line treatment of mesothelioma. Chemotherapy options are limited and include gemcitabine, vinorelbine and other antifolate compounds [Zucali P A, Ceresoli G L, Garassino I, De Vincenzo F, Cavina R, Campagnoli E Cancer 2008; 112(7):1555-1561].
Indeed, there is a very high unmet medical need for new potent agents for the treatment of mesotheliomas. The present invention addresses this problem.